Unravelling short stature in pediatrics: the crucial role of genetic perspective

Understanding short stature

In the realm of contemporary medicine, the pursuit of precision and accuracy continues to drive advancements in genetic testing. For paediatric patients presenting with short stature, a condition often influenced by a myriad of genetic factors, the diagnostic landscape has undergone a transformation with the emergence of chromosomal microarray analysis (CMA) and exome sequencing (ES). This approach not only expedites the diagnostic process but also provides the opportunity to identify common genetic patterns in individuals with short stature, paving the way for more personalized and effective treatments.

In this editorial commentary, I will analyze the recent paper authored by Li et al., delving into the dynamic role of contemporary technologies in deciphering the genetic intricacies associated with short stature (1). The exploration encompasses an in-depth assessment of their diagnostic performance, challenges encountered, and the significant potential they bear for advancing patient care. This editorial commentary also aims to provide a comprehensive analysis of the comparative aspects of these two genetic testing modalities, delving into the specific advantages and limitations of each of them in the context of short stature.

Short stature, defined as a height that is less than 2 standard deviations (SDs) from the mean for the respective age and gender (1,2). The aetiology of short stature is multifactorial and can result from genetic factors, hormonal factors such as growth hormone, thyroid hormones, and cortisol, and a spectrum of environmental factors (prenatal and postnatal), or a combination of both. While familial short stature and constitutional growth delay are common conditions of short stature, a subset of cases involves genetic syndromes and disorders that necessitate a comprehensive genetic evaluation for accurate diagnosis and appropriate management, particularly in cases of severe short stature with associated dysmorphic features. A significant proportion of short stature cases have an underlying genetic aetiology with more than 250 genes implicated in its pathogenesis such as SHOX, GH1, IGF1, IGF1R, GHR or FGFR3, among others. Therefore, identifying the genetic basis of short stature is critical for establishing accurate diagnoses, informing prognosis, and guiding personalized management strategies (1-6). The utility of ES and CMA in the study of short stature extends beyond diagnosis. The information obtained through these advanced techniques also opens the door to potential therapeutic research.

The systematic review and meta-analysis from Li et al., involving 20 studies and a total of 2,420 patients with short stature, found an overall diagnostic yield of 27.1% for ES and 13.6% for CMA. No statistically significant difference was observed between first-tier and last-resort groups for either ES or CMA. These results provide evidence supporting the diagnostic efficacy of ES and CMA in patients with short stature, trying to serve as a valuable guidance for clinicians in recommending genetic tests.

I think that while the methodology of the study regarding included and excluded articles seems appropriate, a significant limitation lies in the great heterogeneity observed within the spectrum of short stature. Most classifications of short stature consider factors to guide the diagnosis and management of patients with short stature, as they help identify patients with a higher suspicion of syndromic causes, and the diagnostic yield based on genetic testing.

Some of the most frequent genetic syndromes associated with short stature are: Turner, Down, 22q11.2 deletion, Noonan, Williams, Silver-Russell and Prader-Willi syndromes, SHOX deficiency and achondroplasia, among others (2-4).

Comparative analysis

CMA is a genomic technique used to detect chromosomal abnormalities and copy number variations (CNVs) across the entire genome. It has traditionally served as a screening tool in the genetic diagnostic arsenal. It excels in detecting submicroscopic chromosomal imbalances and CNV, providing a comprehensive view of the genome (7,8).

CMA is the most widely used genetic screening test that rules out various genetic syndromes associated with short stature. Over time, in many types of short stature and based on associated clinical signs, it has been losing strength and giving way to ES.

ES is a genomic technique of next-generation-sequencing used to analyse the protein-coding regions of an individual’s genome. These regions represent only about 1–2% of the entire genome but harbour the majority of disease-causing variants. It has emerged as a powerful tool for identifying pathogenic variants associated with genetic disorders. In the context of short stature, ES allows clinicians to scrutinize a vast array of genes implicated in growth and development. Its ability to uncover rare or novel mutations makes it particularly valuable in cases where traditional genetic testing methods may fall short. It has proven to be more useful in cases when short stature is associated with microcephaly, body disproportions, skeletal dysplasias, developmental delay, small for gestational age that does not exhibit catch-up growth and in cases of severe short stature (below −3 SD) (9-14).

Li et al.’s research investigates the diagnostic yield of ES in patients with short stature but does not delve into the challenges encountered in interpreting genetic variants, the significance of variant prioritization strategies, and the ethical considerations related to disclosing incidental findings. Additionally, it would be highly beneficial to ascertain whether the studies included in ES employed clinical ES (CES) or whole ES (WES). CES focuses on sequencing a curated subset of exomes from genes associated with human diseases, while WES covers the entire exome, providing a broader analysis and including genes unrelated to pathology to date.

A critical examination of the diagnostic performance of ES and CMA in patients with short stature involves an exploration of their respective strengths and weaknesses, including cost-effectiveness aspects.

Prior to employing ES and CMA, clinicians assessing a child with short stature should take into consideration other genetic conditions that may not be readily identifiable through these methodologies. In the case of suspecting Turner syndrome, SHOX deficiency, and Silver-Russell syndrome, relevant studies should be requested such as karyotype, sequencing and multiplex ligation-dependent probe amplification (MLPA) of the SHOX gene, and methylation-specific MLPA (MS-MLPA) of Silver-Russell syndrome (11,12).

Diagnostic yield is higher in ES than with CMA, although it appears that there are no significant differences between them as first or second-choice tests, or when assessed over time. With this, other aspects must be taken into consideration, such as equity in accessibility to both tests, the cost of each, and the specific characteristics of each hospital requesting the genetic test.

It is also important to note that some CNVs may not be accurately detected through technology-dependent ES or CMA, depending on the size. Therefore, within the algorithms for short stature, other studies such as genome sequencing, long-reads sequencing, or optical genomic mapping should be considered when ES and CMA have yielded negative results (7-12).

Within this comparison, it is also important to consider the age factor. Including patients with short stature of different ages, and sometimes even including prenatal or new-born parameters, in the same study limits the conclusions that can be drawn. Exogenous factors such as nutrition or infections do not play the same role at all ages. Grouping patients by age to assess the diagnostic performance of different studies might be a more accurate approach (13,14). This phenotype-driven approach in short stature involves evaluating the individual’s physical characteristics and associated symptoms or signs to guide diagnostic investigations. This approach considers factors such as the onset age of short stature, presence of microcephaly and body disproportions.

Another limitation that we encounter is that there is no consensus on a list of syndromes with short stature. This arises from the complexity and variability of presentations within the short stature spectrum, which often overlap with other genetic and medical conditions. Establishing a standardized and comprehensive list of syndromes associated with short stature would facilitate accurate diagnosis, improve patient care, and enhance research efforts aimed at understanding the underlying genetic mechanisms. Additionally, it could create diagnostic algorithms for patients with short stature, leading to a loss of the overall perspective for recommending the most appropriate studies. Finally, consensus on the classification of short stature syndromes would aid in the development of targeted therapeutic interventions and genetic counselling strategies, ultimately benefiting individuals affected by these conditions and their families.

Phenotype-driven

Although it is indisputable that advancements in genetic technology have provided the means to identify and treat numerous children with short stature, it becomes imperative to underscore the profound value of clinical and dysmorphic evaluation. Whenever feasible, a phenotype-driven approach to studies proves to be more direct, expeditious, and reliable, especially when under the purview of a clinical geneticist. Alternatively, the expertise of an experienced endocrinologist or another specialist trained in the intricacies of short stature remains an invaluable asset in navigating the complexities of these cases.

The nuanced nature of dysmorphic features and their correlation with genetic variations necessitates a meticulous clinical examination, this examination requires the expertise of a clinical geneticist, whose trained eye can discern subtle indicators that may not be readily apparent through a purely molecular approach. This emphasis on clinical assessment complements and enriches the genetic insights garnered through technological advancements.

While genetic analyses contribute significantly to our understanding of short stature aetiologies, the integration of clinical expertise is essential for a comprehensive evaluation. The collaboration between clinical geneticists, endocrinologists, and other specialists not only ensures a holistic approach but also facilitates a more nuanced and personalized understanding of each case. This multidisciplinary approach not only reinforces the accuracy of diagnoses but also paves the way for tailored and effective treatment strategies, ultimately enhancing the overall care and outcomes for children with short stature.

The ability to discern whether we are dealing with isolated or syndromic short stature seems to be a first step in guiding short stature algorithms and enhancing diagnostic performance. Within syndromic causes, emphasizing the presence of microcephaly, body disproportions, developmental delay, severe short stature, small for gestational age that does not exhibit catch-up growth or prenatal/postnatal origin helps physicians better direct studies and narrow down diagnostic options for improved genotype-phenotype correlation (13-19).

Beyond the laboratory setting, the diagnostic information derived from ES and array analysis has far-reaching implications for clinical management. Early and accurate diagnosis not only guides appropriate interventions and treatments but also facilitates genetic counselling for affected individuals and their families.

Challenges and future directions

No technological advancement comes without challenges, and the landscape of genetic testing for short stature is no exception. I consider that there are several challenges that clinicians face with the advancement of genetic technology and the increasing diagnoses of genetic syndromes, including ultra-rare diseases. These difficulties may include interpreting complex genetic data, navigating variant of uncertain significance (VUS) scenarios, and addressing the psychosocial impact on patients and families (19,20).

Alongside all these challenges, we cannot overlook two priority aspects to drive an increase in diagnoses for children with genetically caused short stature: the training of paediatricians and other professionals in clinical genetics, and the impulsion of translational research. Without well-trained paediatricians capable of comprehensively evaluating a child with seemingly syndromic short stature, we may miss the opportunity to better direct the study and provide more accurate guidance to the patient and their families. Simultaneously, if we have more diagnosed patients but without therapeutic advancements, we may miss the opportunity to offer measures to improve their quality of life, not only in terms of stature but also in overall quality of life.

However, as we could celebrate these advances, it is crucial to advocate for equitable access to these technologies. Advanced genetic research should not be confined to a privileged few; it should be accessible to all those who could benefit from it. Equity in genetic health is an ethical imperative that must be addressed as a priority. One strategy may be to allocate dedicated funding for rare disease research and treatment, establish specialized centers for care, and offer financial assistance programs. Additionally, raising awareness and fostering collaboration among stakeholders can help improve access to treatment for patients with short stature.

As we traverse the intricate landscape of genetic diagnostics for short stature, the roles of ES and CMA emerge as pivotal in unravelling the genetic tapestry (18-20). By fostering a deeper understanding of the genetic underpinnings of short stature, we embark on a journey towards more precise diagnoses, informed interventions, and improved outcomes for patients and families grappling with this complex condition.

Is it time to position ES as the primary diagnostic test for any paediatric patient with short stature? As discussed in this commentary, it is not an easy answer and is subject to various conditions related to the patient, the professional, and the institution. Nevertheless, it seems plausible to consider replacing CMA by ES as a first-line test as a good strategy to achieve faster genetic diagnoses. I would recommend that ES be performed as a first-tier test when short stature is associated with microcephaly, developmental delay, body disproportions, skeletal dysplasias, small for gestational age that does not exhibit catch-up growth and severe degree.

In conclusion, the good use of genetic testing in clinical conditions such as short stature represent a new era in understanding and addressing personalized medicine. These tools not only facilitate early diagnosis but also open opportunities for achieving more precise and personalized treatments. As we navigate this exciting genetic territory, we must ensure that its benefits reach everyone, ensuring a healthier and more equitable future for those affected by short stature.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-46/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-46/coif). The author has no conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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